Age-related skeletal muscle atrophy (i.e., sarcopenia) accelerates beyond the fifth decade and leads to functional limitations and comorbidities that markedly impair quality of life. Resistance training has shown the most promise among treatments to combat sarcopenia as it enhances muscle function, but induces varying degrees of muscle hypertrophy. The overarching aim is to build on current work in older (60-75 yr) vs. young (20-35 yr) women and men by advancing the understanding of resistance training adaptations using a dose-response approach in older adults, ultimately leading to optimal training program design to combat sarcopenia. A novel resistance training model will be explored (versus 3 others) that is predicted to surpass previous attempts to improve key losses of function associated with sarcopenia (strength, power, and fatigue resistance) by maximizing its impact on the root sarcopenia itself (i.e. by increasing muscle mass and integrity). Myofiber hypertrophy requires net muscle protein synthesis and, as demonstrated during the current funding period/advanced fiber expansion is facilitated by nuclear addition. Over the past 4.25 years of support, key cellular/molecular events within skeletal muscle that likely drive these processes have been identified, and several have been shown to respond in an age- and gender-dependent manner to resistance exercise. Four 30-wk resistance training models will be tested in 60-75 yr adults (n=88: 22 per model;11 women, 11 men) after 4 wk of pre-training to determine which model maximizes muscle growth/regeneration. There are three specific aims: 1) to evaluate the gender-specific efficacy of each model based on muscle hypertrophy and performance;2) to assess net muscle protein synthesis and myonuclear addition, along with key cellular/molecular myogenic processes, driving differences in growth among the models in a potentially gender-specific manner;and 3) to translate the findings of aim 1 to clinically important outcomes by determining the degree to which non-traditional training programs improve mobility function. Relevance: As the U.S. population 65+ yr of age expands to 70 million by 2030, sarcopenia will become a large-scale public health issue as the number of older adults suffering functional limitations will reach epidemic proportions in the absence of effective treatments. The proposed research is a critical step toward defining a broadly applicable intervention to maximize gains in muscle mass and function among elderly.